H. influenzae type b (Hib), pneumococci and meningococci are the major bacterial causes of meningitis, bacteremia, pneumonia and otitis media in children. The prevention of infections caused by these pathogens would be an important advance. Although vaccines of improved immunogenicity are being developed, they may not reliably induce a protective antibody response in very young infants or in immunocompromised children. Passive immunization with a human hyperimmune globulin offers an attractive alternative which could be used alone or in conjuction with active immunization in high-risk groups. We have prepared a human hyperimmune globulin termed Bacterial Polysaccharide Immune Gobulin (BPIG) from the pooled plasma of donors immunized with polyvalent pneumococcal, meningococcal and Hib vaccines. A single dose of BPIG produces "protective" levels of antibody to Hib for approximately four months. We will examine the efficacy of BPIG in Native American infants known to be at high risk of infections caused by pyogenic bacteria. Infants will be randomized to receiving BPIG or placebo at 2, 6 and 10 months. The incidence of bacteriologically documented Hib disease (the major outcome), and pneumococcal disease, other bacteriologically documented infections, pneumonia and otitis media will be compared in the two groups. In order to fully evaluate the mechanisms of protection and the effects of passive immune globulin on the development of the immune system, we will compare in placebo and BPIG treated infants (a) the rates of acquisition and duration of carriage of Hib in the propharynx, (b) the serum antibody responses to oropharyngeal colonization and to invasive infection with Hib, (c) the rates of acquisition of "natural" antibody to Hib and pneumococcal capsular antigens and (d) the active immune responses to routine childhood immunizations and to Hib vaccine. The clinical data and specimens collected during the study will also enable us to examine several additional questions relating to local immunity and the immunogenetics of the antibody response to Hib. Documentation of the efficacy of hyperimmune globulin in Native American infants will provide a rationale for the use of this material in other high-risk groups including infants with sickle cell disease or asplenia, children with congenital or acquried immunodeficiences, recurrent bacterial pneumonias or middle ear infections and contacts of children with Hib infections.